2-222201817-C-CA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_181458.4(PAX3):c.1420+126_1420+127insT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 127,078 control chromosomes in the GnomAD database, including 3,188 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.24 (3188 hom., cov: 24)
  • Exomes 𝑓: 0.28 (438 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAX3 NM_181458.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.474

Genes affected

PAX3 (HGNC:8617): (paired box 3) This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. Mutations in paired box gene 3 are associated with Waardenburg syndrome, craniofacial-deafness-hand syndrome, and alveolar rhabdomyosarcoma. The translocation t(2;13)(q35;q14), which represents a fusion between PAX3 and the forkhead gene, is a frequent finding in alveolar rhabdomyosarcoma. Alternative splicing results in transcripts encoding isoforms with different C-termini. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 2-222201817-C-CA is Benign according to our data. Variant chr2-222201817-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 334553.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX3	NM_181458.4	c.1420+126_1420+127insT		intron_variant		ENST00000392070.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX3	ENST00000392070.7	c.1420+126_1420+127insT		intron_variant		1	NM_181458.4	A1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 30384 AN: 127024 Hom.: 3182 Cov.: 24

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.327

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.228

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.275 AC: 329055 AN: 1194964 Hom.: 438 Cov.: 0 AF XY: 0.274 AC XY: 162486 AN XY: 593592

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.188

Gnomad4 ASJ exome AF: 0.278

Gnomad4 EAS exome AF: 0.263

Gnomad4 SAS exome AF: 0.273

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.282

Gnomad4 OTH exome AF: 0.275

GnomAD4 genome AF: 0.239 AC: 30416 AN: 127078 Hom.: 3188 Cov.: 24 AF XY: 0.241 AC XY: 14723 AN XY: 61016

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.310

Gnomad4 SAS AF: 0.312

Gnomad4 FIN AF: 0.250

Gnomad4 NFE AF: 0.252

Gnomad4 OTH AF: 0.228

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Craniofacial-deafness-hand syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Waardenburg syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs368725878; hg19: chr2-223066536;